Dysregulated BCL9 Controls Tumorigenicity and Ferroptosis Susceptibility by Binding With Nrf2 in Thyroid Carcinoma.

Thyroid carcinoma (TC) is the most common malignant tumor of the endocrine system with increasing incidence. In this study, we found that BCL9 is markedly upregulated in human TC tumors and its expression is positively corrected with the process of TC. Functionally, we found that overexpression of BCL9 promoted the proliferation and migration of TC cells, while reduced the sensitivity of TC cells to ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation and implicated as a novel cancer therapeutic strategy. Mechanistically, the co-immunoprecipitation assay determined that BCL9 could bind to Nrf2 which has been confirmed to play an important role in ferroptosis. Furthermore, we demonstrated that silence of BCL9 could decrease Nrf2 expression, and then affect the expression of the downstream genes of Nrf2, ultimately induce ferroptosis. Importantly, we confirmed the effects of BCL9 on TC tumors in vivo. Overall, this study unveils the functional role and clinical significance of BCL9 in TC progression, and highlights the potential of targeting BCL9/Nrf2 ferroptosis axis as a novel therapeutic strategy for TC treatment.

Disease-modifying drugs for multiple sclerosis and subsequent health service use.

OBJECTIVE: We assessed the relationship between the multiple sclerosis (MS) disease-modifying drugs (DMDs) and healthcare use. METHODS: Persons with MS (aged ⩾18 years) were identified using linked population-based health administrative data in four Canadian provinces and were followed from the most recent of their first MS/demyelinating event or 1 January 1996 until the earliest of death, emigration, or study end (31 December 2017 or 31 March 2018). Prescription records captured DMD exposure, examined as any DMD, then by generation (first-generation (the injectables) or second-generation (orals/infusions)) and individual DMD. The associations with subsequent all-cause hospitalizations and physician visits were examined using proportional means model and negative binomial regression. RESULTS: Of 35,894 MS cases (72% female), mean follow-up was 12.0 years, with person-years of DMD exposure for any, or any first- or second-generation DMD being 63,290, 54,605 and 8685, respectively. Any DMD or any first-generation DMD exposure (versus non-exposure) was associated with a 24% lower hazard of hospitalization (adjusted hazard ratio, aHR: 0.76; 95% confidence intervals (CIs): 0.71-0.82), rising to 29% for the second-generation DMDs (aHR: 0.71; 95% CI: 0.58-0.88). This ranged from 18% for teriflunomide (aHR: 0.82; 95% CI: 0.67-1.00) to 44% for fingolimod (aHR: 0.56; 95% CI: 0.36-0.87). In contrast, DMD exposure was generally not associated with substantial differences in physician visits. CONCLUSION: Findings provide real-world evidence of a beneficial relationship between DMD exposure and hospitalizations.

Factors associated with early nonpersistence among patients experiencing side effects from a new medication.

BACKGROUND: Drug discontinuation (i.e., nonpersistence) is often attributed to the emergence of adverse effects. However, it is not known whether other factors increase the risk of nonpersistence when adverse effects occur. OBJECTIVES: To identify factors associated with early nonpersistence among patients experiencing adverse effects from newly prescribed medications. METHODS: A questionnaire was mailed to new users of antihypertensive, antihyperglycemic, and lipid-lowering medications in Saskatchewan, Canada, between 2019 and 2020. Only respondents experiencing adverse effects were included. Responses were compared between the nonpersistent group (i.e., people who had discontinued their medication) and the persistent group (i.e., those who were taking their medication at the time of the survey). Statistically significant factors were tested in multivariable logistic regression models. Odds ratios (ORs) and 95% CIs were reported. RESULTS: Of the 3973 returned questionnaires, 813 respondents experienced adverse -effects from their new medication and were included in the study. Of these, 143 respondents (17.5%) had stopped their medication at the time of survey completion; most discontinuations (72.1%) occurred within 1 month of the first dose. Nonpersistent patients were older, had lower income, and were less likely to be taking an antihyperglycemic medication. After covariate adjustment, 6 factors were independently associated with nonpersistence: age less than 65 years (OR 1.56 [95% CI 1.01-2.41]), female sex (1.67 [1.08-2.59]), health condition not considered dangerous (2.09 [1.25-3.51]), medication not considered important for health (6.90 [4.40-10.84]), failure to expect adverse effects before starting medication (2.67 [1.74-4.10]), and taking 2 or more medications (0.45 [0.27-0.73]). CONCLUSION: Despite the strong link between the emergence of adverse effects and early nonpersistence, our findings confirm that this association is highly influenced by several factors external to the physical experiences caused by the new medication.

Sociodemographic and Geographic Factors Associated With Non-Obstetrical Ultrasound Imaging Utilization: A Population-Based Study.

OBJECTIVE: Ultrasound is one of the most commonly used imaging modalities, though some populations face barriers in accessing ultrasound services, potentially resulting in disparities in utilization. The objective of this study was to assess the association between sociodemographic and geographic factors and non-obstetrical ultrasound utilization in the province of Saskatchewan, Canada. METHODS: All non-obstetrical ultrasound exams performed from 2014 to 2018 in Saskatchewan, Canada were retrospectively identified from province-wide databases. Univariate and multivariate Poisson regression analyses were performed to assess the association between ultrasound utilization and sex, age, First Nations status, Charlson Comorbidity Index, urban vs. rural residence, geographic remoteness, and neighborhood income. RESULTS: A total of 1,324,846 individuals (5,857,044 person-years) were included in the analysis. Female sex (adjusted incidence rate ratio [aIRR], 2.20; 95% confidence interval [CI], 2.19-2.22), age (aIRR, 4.97; 95% CI, 4.90-5.05 for ≥57 years vs. <11 years), comorbidities (aIRR, 4.36 for Charlson Comorbidity Index >10 vs. 0; 95% CI, 3.78-5.03), and higher neighborhood income (aIRR, 1.04; 95% CI, 1.02-1.05 for highest vs. lowest quintile) were associated with higher rates of ultrasound utilization. Individuals who were status First Nations (aIRR, 0.91; 95% CI, 0.90-0.92) or resided in geographically remote areas (aIRR, 0.87 for most vs. least remote; 95% CI, 0.83-0.91) had lower rates of ultrasound utilization. Individuals who lived in a rural area also had lower rates of ultrasound utilization (aIRR, 0.93; 95% CI, 0.92-0.94). CONCLUSION: Substantial disparities exist in non-obstetrical ultrasound utilization among individuals in low-income neighborhoods, status First Nations individuals, and individuals in rural and remote communities.

Resident-Level Predictors of Dementia Pharmacotherapy at Long-Term Care Admission: The Impact of Different Drug Reimbursement Policies in Ontario and Saskatchewan: Prédicteurs de la pharmacothérapie de la démence au niveau des résidents lors de l'hospitalisation dans des soins de longue durée : l'impact de différentes politiques de remboursement des médicaments en Ontario et en Saskatchewan.

OBJECTIVES: Cholinesterase inhibitors (ChEIs) and memantine are approved for Alzheimer disease in Canada. Regional drug reimbursement policies are associated with cross-provincial variation in ChEI use, but it is unclear how these policies influence predictors of use. Using standardized data from two provinces with differing policies, we compared resident-level characteristics associated with dementia pharmacotherapy at long-term care (LTC) admission. METHODS: Using linked clinical and administrative databases, we examined characteristics associated with dementia pharmacotherapy use among residents with dementia and/or significant cognitive impairment admitted to LTC facilities in Saskatchewan (more restrictive reimbursement policies; n = 10,599) and Ontario (less restrictive; n = 93,331) between April 1, 2009, and March 31, 2015. Multivariable logistic regression models were utilized to assess resident demographic, functional, and clinical characteristics associated with dementia pharmacotherapy. RESULTS: On admission, 8.1% of Saskatchewan residents were receiving dementia pharmacotherapy compared to 33.2% in Ontario. In both provinces, residents with severe cognitive impairment, aggressive behaviors, and recent antipsychotic use were more likely to receive dementia pharmacotherapy; while those who were unmarried, admitted in later years, had a greater degree of frailty, and recent hospitalizations were less likely. The direction of the association for older age, rural residency, medication number, and anticholinergic therapy differed between provinces. CONCLUSIONS: While more restrictive criteria for dementia pharmacotherapy coverage in Saskatchewan resulted in fewer residents entering LTC on dementia pharmacotherapy, there were relatively few differences in the factors associated with use across provinces. Longitudinal studies are needed to assess how differences in prevalence and characteristics associated with use impact patient outcomes.

Measuring the Influence of Side Effect Expectations, Beliefs, and Incident Side Effects on the Risk for Drug Discontinuation Among Individuals Starting New Medications, a Cross-sectional Study.

Purpose: To measure the impact of beliefs, expectations, side effects, and their combined effects on the risk for medication nonpersistence. Patients and methods: Using a cross-sectional design, individuals from Saskatchewan, Canada who started a new antihypertensive, cholesterol-lowering, or antihyperglycemic medication were surveyed about risk factors for nonpersistence including: (a) beliefs measured by a composite score of three questions asking about the threat of the condition, importance of the drug, and harm of the drug; (b) incident side effects attributed to treatment; and (c) expectations for side effects before starting treatment. Descriptive statistics and logistic regression models were used to quantify the influence of these risk factors on the outcome of nonpersistence. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Results: Among 3,029 respondents, 5.8% (n=177) reported nonpersistence within four months after starting the new drug. After adjustment for numerous covariates representing sociodemographics, health-care providers, medication experiences and beliefs, both negative beliefs (OR: 7.26, 95%CI: 4.98-10.59) and incident side effects (OR: 8.00, 95%CI: 5.49-11.68) were associated with the highest odds of nonpersistence with no evidence of interaction. In contrast, expectations for side effects before starting treatment exhibited an important interaction with incident side effects following treatment initiation. Among respondents with incident side effects (n=741, 24.5%), the risk for early nonpersistence was 11.5% if they indicated an expectation for side effects before starting the medication compared to 23.6% if they did not (adjusted OR: 0.38, 95%CI: 0.25-0.60). Conclusion: Expectations for side effects may be a previously unrecognized but important marker of the probability to persist with treatment. A high percentage of new medication users appeared unprepared for the possibility of side effects from their new medication making them less resilient if side effects occur.

Adverse Events Associated With Disease-Modifying Drugs for Multiple Sclerosis: A Multiregional Population-Based Study

BACKGROUND AND OBJECTIVES: It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common adverse events occurring over the short-term can be captured, and the quality of reporting has been variable. We examined the relationship between the DMDs for MS and potential adverse events in a multiregion population-based study. METHODS: We identified people with MS using linked administrative health data from 4 Canadian provinces. MS cases were followed from the most recent of first MS or related demyelinating disease event on January 1, 1996, until the earliest of emigration, death, or December 31, 2017. DMD exposure primarily comprised ß-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. We examined associations between DMD exposure and infection-related hospitalizations and physician visits using recurrent events proportional means models and between DMD exposure and 15 broad categories of incident adverse events using stratified multivariate Cox proportional hazard models. RESULTS: We identified 35,894 people with MS. While virtually all DMDs were associated with a 42%-61% lower risk of infection-related hospitalizations, there was a modest increase in infection-related physician visits by 10%-33% for select DMDs. For incident adverse events, most elevated risks involved a second-generation DMD, with alemtuzumab's hazard of thyroid disorders being 19.42 (95% CI 9.29-36.51), hypertension 4.96 (95% CI 1.78-13.84), and cardiovascular disease 3.72 (95% CI 2.12-6.53). Natalizumab's highest risk was for cardiovascular disease (adjusted hazard ratio [aHR] 1.61; 95% CI 1.24-2.10). For the oral DMDs, fingolimod was associated with higher hazards of cerebrovascular (aHR 2.04; 95% CI 1.27-3.30) and ischemic heart diseases (aHR 1.64; 95% CI 1.10-2.44) and hypertension (aHR 1.73; 95% CI 1.30-2.31); teriflunomide with higher hazards of thyroid disorders (aHR 2.30; 95% CI 1.11-4.74), chronic liver disease (aHR 1.94; 95% CI 1.19-3.18), hypertension (aHR 1.76; 95% CI 1.32-2.37), and hyperlipidemia (aHR 1.61; 95% CI 1.07-2.44); and from complementary analyses (in 1 province), dimethyl fumarate with acute liver injury (aHR 6.55; 95% CI 1.96-21.87). DISCUSSION: Our study provides an extensive safety profile of several different DMDs used to treat MS in the real-world setting. Our findings not only complement those observed in short-term clinical trials but also provide new insights that help inform the risk-benefit profile of the DMDs used to treat MS in clinical practice. The results of this study highlight the continued need for long-term, independent safety studies of the DMDs used to treat MS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS, while DMD exposure reduces the risk of infection-related hospitalizations, there are increased risks of infection-related physician visits and incident adverse events for select DMDs.

The Impact of Age and Sex Concordance Between Patients and Physicians on Medication Adherence: A Population-Based Study.

PURPOSE: Age or sex concordance (same sex or same age range) may also be associated with medication adherence but was not fully investigated. We aim to quantify the impact of age and sex concordance on optimal adherence to statin medications. PATIENTS AND METHODS: A retrospective cohort study was conducted using population-based health administrative data from Saskatchewan, Canada. Participants were individuals newly initiated on statin medications between January 1, 2012, and December 31, 2017. The outcome was optimal adherence (proportion of days covered ≥ 80%) measured at one year after the first statin claim. The independent variables were sex and age concordance (age within five years) between patients and prescribers. The association between adherence outcome and sex/age concordance was analyzed by multivariable logistic regression models using generalized estimating equations controlled by a package of potential confounding factors. RESULTS: Among 51,874 new statin users, 20.6% (n = 10,710) were age concordant with prescriber. The vast majority of age concordance occurred in patients younger than 66 years (88.6%, 9,486/10,710). Sex concordance was observed in 62.8% (n = 32,551) of patients and age-sex combined concordance in 13.2% (n = 6,856). Among patients younger than 66 years (n = 36,641/51,874, 70.6%), age concordance did not have a significant impact on optimal adherence [adjusted OR (aOR) = 1.02, 95% CI 0.97 to 1.07]. Weak association between sex concordance (aOR = 1.05, 95% CI 1.00 to 1.11), and age-sex combined concordance (aOR = 1.05, 95% CI 0.99 to 1.12) was observed. CONCLUSION: Age and sex concordance were not statistically significant predictors of optimal statin adherence. However, a weak association was detected for sex concordance. Future studies should examine this factor in different health care settings.

An integrated continuity of care measure improves performance in models predicting medication adherence using population-based administrative data.

OBJECTIVES: Continuity of care (COC) is considered an important determinant of medication adherence based on measures such as the usual provider continuity index (UPCI) that are derived exclusively from physician visit claims. This study aimed to: a) determine if high UPCI values predict physicians who deliver different clinical services; and b) compare UPCI with an integrated COC measure capturing physician visits, prescribing, and a complete medical examination in a multivariable model of patients receiving statin medications. METHODS: This was a retrospective cohort study of new statin users between 2012 and 2017 in Saskatchewan, Canada. We calculated sensitivity/specificity of a high UPCI value for predicting physicians who were prescribers of statins and/or providers of complete medical examinations. Next, we used logistic regression models to test two measures of COC (high UPCI value or an integrated COC measure) on the outcome of optimal statin adherence (proportion of days covered ≥80%). The DeLong test was used to compare predictive performance of the two models. RESULTS: Among 55,144 new statin users, a high UPCI was neither a sensitive or specific marker of physicians who prescribed statins or performed a complete medical examination. The integrated COC measure had a stronger association with optimal adherence [adjusted odds ratio (OR) = 1.56, 95% confidence interval (CI) 1.50 to 1.63] than UPCI (adjusted OR = 1.23, 95% CI 1.19 to 1.28), and improved predictive performance of the adherence model. CONCLUSION: The number of physician visits alone appears to be insufficient to represent COC. An integrated measure improves predictive performance for optimal medication adherence in patients initiating statins.

Physician influence on medication adherence, evidence from a population-based cohort.

BACKGROUND: The overall impact of physician prescribers on population-level adherence rates are unknown. We aimed to quantify the influence of general practitioner (GP) physician prescribers on the outcome of optimal statin medication adherence. METHODS: We conducted a retrospective cohort study using health administrative databases from Saskatchewan, Canada. Participants included physician prescribers and their patients beginning a new statin medication between January 1, 2012 and December 31, 2017. We grouped prescribers based on the prevalence of optimal adherence (i.e., proportion of days covered ≥ 80%) within their patient group. Also, we constructed multivariable logistic regression analyses on optimal statin adherence using two-level non-linear mixed-effects models containing patient and prescriber-level characteristics. An intraclass correlation coefficient was used to estimate the physician effect. RESULTS: We identified 1,562 GPs prescribing to 51,874 new statin users. The median percentage of optimal statin adherence across GPs was 52.4% (inter-quartile range: 35.7% to 65.5%). GP prescribers with the highest patient adherence (versus the lowest) had patients who were older (median age 61.0 vs 55.0, p<0.0001) and sicker (prior hospitalization 39.4% vs 16.4%, p<0.001). After accounting for patient-level factors, only 6.4% of the observed variance in optimal adherence between patients could be attributed to GP prescribers (p<0.001). The majority of GP prescriber influence (5.2% out of 6.4%) was attributed to the variance unexplained by patient and prescriber variables. INTERPRETATION: The overall impact of GP prescribers on statin adherence appears to be very limited. Even "high-performing" physicians face significant levels of sub-optimal adherence among their patients.

Sociodemographic and Geographic Disparities in Obstetrical Ultrasound Imaging Utilization: A Population-based Study.

RATIONALE AND OBJECTIVES: Obstetrical ultrasound imaging is an important part of prenatal care, though not all patients have readily available access to ultrasound services. This study aimed to assess the association between sociodemographic and geographic factors and (1) having a second trimester complete obstetrical ultrasound and (2) overall obstetrical ultrasound utilization. METHODS: All pregnancies and obstetrical ultrasound exams billed from 2014-2018 in Saskatchewan, Canada were identified from province-wide databases. Generalized estimating equation (GEE) models with binomial and Poisson distributions were used to identify factors associated with having a second trimester ultrasound and overall obstetrical ultrasound utilization, respectively. RESULTS: 80,536 pregnancies from 57,881 individuals were included. Of 57,186 pregnancies carried to ≥23 weeks, a second trimester ultrasound was performed in 50,180 (87.7%). Patients living in rural areas (adjusted odds ratio [aOR], 0.70; 95% confidence interval [CI], 0.63-0.77; p <0.0001), remote areas (aOR, 0.35 for greatest vs. least remoteness level; 95% CI, 0.32-0.39; p <0.0001), and status First Nations individuals (aOR, 0.50; 95% CI, 0.46-0.53; p <0.0001) were less likely to have a second trimester ultrasound. Patients living in higher income neighbourhoods (aOR, 1.86 for highest vs. lowest quintile; 95% CI, 1.62-2.13; p <0.0001) were more likely to have a second trimester ultrasound. GEE Poisson regression analysis demonstrated these same factors, except rural residence, were associated with overall obstetrical ultrasound utilization. CONCLUSION: Substantial disparities in obstetrical ultrasound utilization exist among patients in remote geographic areas, Indigenous peoples, and patients in low income neighbourhoods. Addressing barriers which these demographic groups face in accessing ultrasound imaging is critical to ensure health equity.

Disease-Modifying Drugs for Multiple Sclerosis and Association With Survival.

BACKGROUND AND OBJECTIVES: We examined the association between the disease-modifying drugs (DMDs) for multiple sclerosis (MS) and survival in a multiregion population-based study. METHODS: We accessed multiple administrative health databases from 4 Canadian provinces. Persons with MS were identified and followed from the most recent of the first MS or demyelinating event or January 1, 1996 (index date), until death, emigration, or December 31, 2017. Association between the first-generation and second-generation DMDs and all-cause mortality was examined using stratified Cox proportional hazard models, reported as adjusted hazard ratios (aHRs). Timing of DMD initiation was explored, with findings reported at 2, 5, or 10 years postindex date, representing very early, early, or late initiation. RESULTS: We identified 35,894 persons with MS; 72% were female. The mean age at index date was 44.5 years (SD = 13.6). The total person-years of follow-up while DMD-exposed was 89,180, and total person-years while unexposed was 342,217. Compared with no exposure, exposure to any DMD or to any first-generation DMD was associated with a 26% lower hazard of mortality (both aHRs 0.74; 95% CI 0.56-0.98), while any second-generation DMD exposure was associated with a 33% lower hazard (aHR 0.67; 95% CI 0.46-0.98). Earlier DMD initiation (beta-interferon or glatiramer acetate vs no exposure) was associated with a significant mortality effect (p < 0.05), while later initiation was not (95% CIs included 1). However, the survival advantage with earlier initiation diminished over time, no longer reaching statistical significance at 15 years postindex date. DISCUSSION: Our study demonstrates an association between the DMDs for MS and improved survival in the real-world setting.

Pharmacokinetics of apixaban and tacrolimus or cyclosporine in kidney and lung transplant recipients.

Apixaban is frequently used off-label in transplant recipients. However, a potential drug interaction exists with the calcineurin inhibitors. We conducted an open-label drug-drug interaction study to determine the pharmacokinetics of apixaban in lung and kidney transplant recipients who were taking a calcineurin inhibitor. A single dose of apixaban 10 mg was administered orally to kidney and lung transplant recipients maintained on either tacrolimus or cyclosporine, and pharmacokinetic parameters were compared to a reference cohort of 12 healthy subjects who used the same apixaban dose and pharmacokinetic blood sampling. Fourteen participants were enrolled (n = 6 kidney, n = 8 lung), with 10 maintained on tacrolimus and four on cyclosporine. Data from 13 participants was usable. Participants were taking triple therapy immunosuppression and had a mean (SD) of 12 (3) medications. Participants receiving tacrolimus and cyclosporine had area under the plasma concentration-time curve from time zero to infinity (AUC0-inf ) geometric least square means (90% confidence interval [CI]) of 4312 (95% CI 3682, 5049) and 5388 (95% CI 3277, 8858), respectively. Compared to healthy subjects, the associated geometric mean ratios (GMRs) for apixaban maximum plasma concentration (Cmax ), AUC from time zero to the last quantifiable concentration (AUC0-tlast ) and AUC0-inf were 197% (95% CI 153, 295), 244% (95% CI 184, 323), and 224% (95% CI 170, 295) for transplant recipients on tacrolimus. The GMR (90% CI) Cmax , AUC0-tlast , and AUC0-inf of apixaban for patients on cyclosporine were 256% (95% CI 184, 358), 287% (95% CI 198, 415), and 280% (95% CI 195, 401). Kidney and lung transplant recipients receiving tacrolimus had higher apixaban exposure. A similar trend was noted for patients receiving cyclosporine, but additional patients are needed to confirm this interaction. Future studies are needed before apixaban can be safely recommended in this population, and the impact of dose staggering should be investigated. This study highlights the importance of pharmacokinetic studies in actual patient populations.

Medication adherence in multiple sclerosis as a potential model for other chronic diseases: a population-based cohort study.

OBJECTIVE: To determine whether better medication adherence in multiple sclerosis (MS) might be due to specialised disease-modifying drug (DMD) support programmes by: (1) establishing higher adherence in MS than in other chronic diseases and (2) determining if higher adherence is associated with patient-specific or treatment-specific factors. DESIGN: Retrospective cohort study with data from 1 January 1996 to 31 December 2015. SETTING: Population-based health administrative data from three Canadian provinces. PARTICIPANTS: Individual cohorts were created using validated case definitions for MS, epilepsy, Parkinson's disease (PD) and rheumatoid arthritis (RA). Subjects were included if they received ≥1 dispensation for a disease-related drug between 1 January 1997 and 31 December 2014. MAIN OUTCOME MEASURES: Proportion of subjects with optimal adherence (≥80%) measured by the medication possession ratio 1 year after the index date (first dispensation of disease-related drug). RESULTS: 126 478 subjects were included in the primary analysis (MS, n=6271; epilepsy, n=55 739; PD, n=21 304; RA, n=43 164). Subjects with epilepsy (adjusted OR, aOR 0.29; 95% CI 0.19 to 0.45), PD (aOR 0.42; 95% CI 0.29 to 0.63) or RA (aOR 0.26; 95% CI 0.19 to 0.35) were less likely to have optimal 1-year adherence compared with subjects with MS. Within the MS cohort, adherence was higher for DMD than for chronic-use non-MS medications, and no consistent patient-related predictors of adherence were observed across all four non-MS medication classes, including having optimal adherence to DMD. CONCLUSIONS: Subjects with MS were significantly more likely to have optimal 1-year adherence than subjects with epilepsy, RA and PD, and optimal adherence appears related to treatment-specific factors rather than patient-related factors. This supports the hypothesis that higher adherence to the MS DMDs could be due to the specialised support programmes; these programmes may serve as a model for use in other chronic conditions.

Characteristics of a population-based multiple sclerosis cohort treated with disease-modifying drugs in a universal healthcare setting.

Background: Relatively little is known about the use of disease-modifying drugs (DMDs) for multiple sclerosis (MS) in the population-based universal healthcare setting. This study aimed to describe the characteristics of a population-based cohort with MS and their DMD exposure in four Canadian provinces. Methods: We identified all adults (aged ≥18 years) with MS using linked population-based health administrative data. Individuals were followed from the most recent of their first MS or demyelinating event or 1 January 1996(study entry), to the earliest of death, emigration, or 31 March 2018(study end). Cohort characteristics examined included sex, age, socioeconomic status, and comorbidity burden. Results: Overall, 10,418/35,894 (29%) of MS cases filled a DMD prescription during the 22-year study period. Most were women (n = 7,683/10,418;74%), and 17% (n = 1,745/10,418) had some comorbidity (Charlson Comorbidity Index≥1) at study entry. Nearly 20% (n = 1,745/10,418) were aged ≥50 when filling their first DMD; the mean age was 39.6 years. Conclusions: Almost 1 in 6 people with MS had at least some comorbidity, and nearly 1 in 6 were ≥50 years old at the time of their first DMD. As these individuals are typically excluded from clinical trials, findings illustrate the need to understand the harms and benefits of DMD use in these understudied groups.

Validation of an algorithm for identifying MS cases in administrative health claims datasets.

OBJECTIVE: To develop a valid algorithm for identifying multiple sclerosis (MS) cases in administrative health claims (AHC) datasets. METHODS: We used 4 AHC datasets from the Veterans Administration (VA), Kaiser Permanente Southern California (KPSC), Manitoba (Canada), and Saskatchewan (Canada). In the VA, KPSC, and Manitoba, we tested the performance of candidate algorithms based on inpatient, outpatient, and disease-modifying therapy (DMT) claims compared to medical records review using sensitivity, specificity, positive and negative predictive values, and interrater reliability (Youden J statistic) both overall and stratified by sex and age. In Saskatchewan, we tested the algorithms in a cohort randomly selected from the general population. RESULTS: The preferred algorithm required ≥3 MS-related claims from any combination of inpatient, outpatient, or DMT claims within a 1-year time period; a 2-year time period provided little gain in performance. Algorithms including DMT claims performed better than those that did not. Sensitivity (86.6%-96.0%), specificity (66.7%-99.0%), positive predictive value (95.4%-99.0%), and interrater reliability (Youden J = 0.60-0.92) were generally stable across datasets and across strata. Some variation in performance in the stratified analyses was observed but largely reflected changes in the composition of the strata. In Saskatchewan, the preferred algorithm had a sensitivity of 96%, specificity of 99%, positive predictive value of 99%, and negative predictive value of 96%. CONCLUSIONS: The performance of each algorithm was remarkably consistent across datasets. The preferred algorithm required ≥3 MS-related claims from any combination of inpatient, outpatient, or DMT use within 1 year. We recommend this algorithm as the standard AHC case definition for MS.

Reduced Out-of-Pocket Costs and Medication Adherence - A Population-Based Study.

BACKGROUND: In 2007, a drug benefit plan for Seniors (SDP) was launched in Saskatchewan, Canada. SDP capped out-of-pocket costs at $15 per prescription for individuals aged 65 and older. OBJECTIVES: To quantify the impact of the SDP on chronic medication adherence.  Methods: A retrospective cohort study was conducted for participants aged 65 or older who were eligible to the SPD, controlled by a younger group aged 40 to 64 who were ineligible. Adherence was measured over 365 days using medication possession ratio (MPR). MPRs were compared between age groups, and between pre and post SDP-launch periods. The odds ratio of optimal adherence (i.e., MPR≥80%) was estimated using logistic regression models with generalized estimating equations (GEE). RESULTS: Between 2005 and 2009, 353,568 adherence observations were observed from 188,109 unique patients. Comparing the post-SDP period vs before, the increase in the odds of optimal medication adherence was significant (OR=1.08, 95% CI: 1.04 to 1.11) and was stronger after excluding patients already receiving medication benefits from other government programs (OR= 1.21, 95% CI: 1.16 to 1.26). The SDP was associated with improved adherence among the subgroup of prevalent medication users (OR=1.08, 95% CI: 1.04 to 1.12), but not incident users (OR=1.05, 95% CI: 0.98 to 1.13). CONCLUSION: Reducing out-of-pocket medication costs for seniors was associated with small improvements in medication adherence across the population.

Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study.

Objective To determine the safety of direct oral anticoagulant (DOAC) use compared with warfarin use for the treatment of venous thromboembolism.Design Retrospective matched cohort study conducted between 1 January 2009 and 31 March 2016.Setting Community based, using healthcare data from six jurisdictions in Canada and the United States.Participants 59 525 adults (12 489 DOAC users; 47 036 warfarin users) with a new diagnosis of venous thromboembolism and a prescription for a DOAC or warfarin within 30 days of diagnosis.Main outcome measures Outcomes included hospital admission or emergency department visit for major bleeding and all cause mortality within 90 days after starting treatment. Propensity score matching and shared frailty models were used to estimate adjusted hazard ratios of the outcomes comparing DOACs with warfarin. Analyses were conducted independently at each site, with meta-analytical methods used to estimate pooled hazard ratios across sites.Results Of the 59 525 participants, 1967 (3.3%) had a major bleed and 1029 (1.7%) died over a mean follow-up of 85.2 days. The risk of major bleeding was similar for DOAC compared with warfarin use (pooled hazard ratio 0.92, 95% confidence interval 0.82 to 1.03), with the overall direction of the association favouring DOAC use. No difference was found in the risk of death (pooled hazard ratio 0.99, 0.84 to 1.16) for DOACs compared with warfarin use. There was no evidence of heterogeneity across centres, between patients with and without chronic kidney disease, across age groups, or between male and female patients.Conclusions In this analysis of adults with incident venous thromboembolism, treatment with DOACs, compared with warfarin, was not associated with an increased risk of major bleeding or all cause mortality in the first 90 days of treatment.Trial registration Clinical trials NCT02833987.